Amidines

ABSTRACT

Compounds having the formula ##STR1## wherein R 1  is aryl and both R 2  groups are hydrogen or alkyl, have useful antiinflammatory activity.

This application is a division of copending U.S. patent application Ser.No. 748,861, filed Dec. 10, 1976.

BRIEF DESCRIPTION OF THE INVENTION

Compounds having the formula ##STR2## and the pharmaceuticallyacceptable salts thereof, have useful antiinflammatory activity. Informula I, and throughout the specification, the symbols are as definedbelow.

R₁ is phenyl or phenyl substituted with one or two methoxy, halogen, ortrifluoromethyl groups.

R₂ is hydrogen or alkyl, or both R₂ groups together form an ethylenegroup.

The term "alkyl", as used throughout the specification, refers to alkylgroups having 1 to 12 carbon atoms.

The term "halogen", as used throughout the specification, refers tofluorine, chlorine, bromine and iodine.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are prepared using as starting materialscompounds having the formulas ##STR3## and

    R.sub.1 --NH.sub.2 .                                       (III)

in formula II, and throughout the specification, both R₃ groups arehydrogen or alkyl.

Reaction of a 6,6'-dialkoxy[1,1'-biphenyl]-3,3'-dicarbonitrile offormula II (R₃ is alkyl) and an aniline derivative of formula III, inthe presence of a reducing agent (sodium hydride is preferred) yieldsthe corresponding compound of formula I wherein R₂ is alkyl. Thereaction can be run in an organic solvent, preferably a polar organicsolvent such as dimethylsulfoxide or dimethylformamide. Conditions underwhich the reaction is run are not critical, and it can conveniently becarried out at room temperature.

Those compounds of formula I wherein R₂ is hydrogen can be prepared bycleaving the alkyl groups of a corresponding diether of formula I(wherein R₂ is alkyl) with an acid. Pyridine hydrochloride has beenfound to be an effective acid reagent.

Those compounds of formula I wherein the R₂ groups together form anethylene group, i.e., compounds having the formula ##STR4## can beprepared by first reacting6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (formula II, R₃ ishydrogen) with a compound having the formula

    X--CH.sub.2 --CH.sub.2 --Y,                                (V)

wherein X and Y are independently selected from halogen (chlorine andbromine are preferred), alkylsulfonate and arylsulfonate, to yield acompound having the formula ##STR5## The reaction can be run at anelevated temperature in an organic solvent, preferably a polar organicsolvent such as dimethylsulfoxide or dimethylformamide, in the presenceof a base, e.g., sodium carbonate.

Reaction of a compound of formula VI and an aniline derivative offormula III in the presence of a reducing agent (sodium hydride ispreferred) yields the corresponding compound of formula IV. The reactioncan be run in an organic solvent, preferably a polar organic solventsuch as dimethylsulfoxide or dimethylformamide. Conditions under whichthe reaction is run are not critical, and it can conveniently be carriedout at room temperature.

The starting materials of formula II are known, or readily prepared inaccordance with art recognized procedures; see, for example, Leupold etal., Ann. Chem., 746, 134-148 (1971).

The pharmaceutically acceptable salts of the compounds of formula I canbe prepared from the corresponding free base using procedures well knownin the art. Acid-addition salts are specifically contemplated, e.g., thehydrohalides (especially the hydrochloride and hydrobromide), sulfate,nitrate, phosphate, tartrate, maleate, fumarate, citrate, succinate,methanesulfonate, benzenesulfonate, toluenesulfonate and the like.

The compounds of formula I, and the pharmaceutically acceptable saltsthereof, are useful for the treatment of inflammation in mammalianspecies, such as rats, dogs, cats, monkeys, etc. Joint tenderness andstiffness (in conditions such as rheumatoid arthritis) can be relievedby the above-described compounds.

The compounds of this invention can be formulated for use asantiinflammatory agents according to accepted pharmaceutical practice inoral dosage forms such as tablets, capsules, elixirs or powders, or inan injectable form in a sterile aqueous vehicle prepared according toconventional pharmaceutical practice. The compounds of this inventioncan be administered in amounts of 100 milligrams per kilogram of animalbody weight per day to 2 grams per kilogram of animal body weight perday, preferably 100 milligrams per kilogram of animal body weight perday to 1 gram per kilogram of animal body weight per day.

The following examples are specific embodiments of this invention.

EXAMPLE 1 6,6'-Dimethoxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide, hydrochloride (1:2)

A mixture of 4.0 g of 6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarbonitrile,1.5 g of sodium hydride (50% suspension in oil), 2.8 g of aniline and 15ml of dimethylsulfoxide is prepared and stirred at room temperature forabout 16 hours under nitrogen. The mixture is then poured into water andthe precipitate which forms is separated with filtration. The residue isrecrystallized twice from 10% hydrochloric acid to yield 7.0 g of thetitle compound which is dried over phosphorous pentoxide under vacuumfor 12 hours, to yield the title compound, melting point 220-230° C dec.

Anal. Calc'd. for C₂₈ H₂₈ N₄ O₂ Cl₂ 4H₂ O: C, 56.47; H, 6.09; N, 9.41;Cl, 11.91. Found: C, 56.27; H, 6.07; N, 9.30; Cl, 11.86.

EXAMPLE 26,6'-Dihydroxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A mixture of 2.5 g of6,6'-dimethoxy-N,N"-diphenyl-[1,1'-biphenyl]-3,3'-dicarboximidamide,monohydrochloride (see Example 1) and 25 g of dry pyridine hydrochlorideis heated at 180° C for 75 minutes. The mixture is then cooled, dilutedwith 10 ml of water and acidified with 10 ml of concentratedhydrochloric acid. The mixture is further diluted with 100 ml of 10%hydrochloric acid and allowed to stand at 0° C for about 16 hours. Thecrystalline material so obtained is recrystallized from dilute HCl (10%hydrochloric acid and water until solution occurs at 100° C) to yield900 mg of the title compound, melting point 306-307° C.

Anal. Calc'd. for C₂₆ H₂₂ N₄ O₂ . 2 HCl: C, 63.03; H, 4.88; N, 11.31;Cl, 14.31. Found: C, 63.09; H, 4.80; N, 11.26; Cl, 14.10.

EXAMPLE 36,6'-Dimethoxy-N,N"-[3-(trifluoromethyl)phenyl][1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A mixture of 4.00 g of6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarbonitrile, 1.5 g of sodiumhydride (50% suspension in mineral oil), and 5.0 g ofm-trifluoromethylaniline is prepared in 15 ml of dimethylsulfoxide andstirred for about 16 hours under nitrogen at room temperature. Theresulting reaction mixture is diluted with water and the precipitatewhich forms is filtered with suction. The residue is purified bysuspension in water followed by acidification and filtration. Thefiltrate is neutralized with 10% sodium hydroxide solution and theprecipitate collected by filtration. This residue is then recrystallizedtwice from 10% hydrochloric acid yielding 2.0 g of the title compound,melting point 220-230° C, dec.

Anal. Calc'd. for C₃₀ H₃₂ N₄ O₄ F₆ Cl₂ : C, 51.66; H, 4.62; N, 8.03; Cl,10.16. Found: C, 51.46; H, 4.52; N, 7.73; Cl, 10.34.

EXAMPLE 4N,N"-Bis(3,5-dimethoxyphenyl)-6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A mixture of sodium hydride (57% in mineral oil, 1.52 g),3,5-dimethoxyaniline (4.6 g), and6,6'-dimethoxy-[1,1'-biphenyl]-3,3'-dicarbonitrile (4.0 g) in anhydrousdimethylsulfoxide (15 ml) is stirred under nitrogen at room temperaturefor 18 hours. The dark oil obtained is poured into water and theresultant precipitate collected by filtration. The solid is slurried inwater and the pH adjusted to pH 5 with 10% hydrochloric acid. Thistreatment dissolves most of the precipitate. The solution is thenfiltered to remove traces of starting material. The solution is madebasic with 10% sodium hydroxide and the resultant precipitate iscollected by filtration and washed with water. This material isrecrystallized twice from 10% hydrochloric acid and once from 5%hydrochloric acid to yield 2.8 g of the title compound, melting point228-230° C, dec.

Anal. Calc'd. for C₃₂ H₃₄ N₄ O₆ . 2 HCl: C, 59.72; H, 5.64; N, 8.71; Cl,11.02. Found: C, 59.97; H, 5.64; N, 8.69; Cl, 10.94.

EXAMPLE 5N,N"-Bis(4-Fluorophenyl)-6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A mixture of 6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarbonitrile (5.0 g)and sodium hydride (1.92 g) is prepared in dimethylsulfoxide (20 ml). Tothis is added, with stirring under nitrogen, a solution ofp-fluoroaniline (3.8 g) dissolved in 10 ml of dimethylsulfoxide. Theaddition is carried out at such a rate as to control the foaming thatoccurs in this reaction. After addition is complete, the mixture isstirred at room temperature for 24 hours and poured into water. Theprecipitate which forms is separated by filtration and the residuewashed on the filter with water. The material is recrystallized twicefrom 10% hydrochloric acid to yield 8.3 g of the title compound, meltingpoint 229° C, dec.

Anal. Calc'd. for C₂₈ H₂₄ F₂ N₄ O₂ . 2 HCl . 2 H₂ O: C, 56.47; H, 5.09;N, 9.41: F, 6.38; Cl, 11.91. Found: C, 56.66; H, 5.14; N, 9.46; F, 6.53;Cl, 11.96.

EXAMPLE 66,7-Dihydro-N,N"-diphenyldibenzo[e,g][1,4]dioxocin-2,11-dicarboximidamide

(A) 6,7-Dihydrodibenzo[e,g][1,4]dioxocin-2,11-dicarbonitrile

A mixture of 6,6'-dihydroxy[1,1'biphenyl]-3,3'-dicarbonitrile (11.8 g),sodium carbonate (10.6 g), and 1,2-dibromoethane (8.4 g) in 250 ml ofanhydrous dimethylformamide is heated at 150° C for 18 hours undernitrogen. The reaction mixture is poured into water and extracted withthree 200 ml portions of dichloromethane. The dichloromethane extractsare combined and washed with 10% sodium hydroxide, water, and brine. Thesolution is filtered through 100 ml of silica gel and concentrated. Theresultant solid is recrystallized from benzene to yield 3.5 g of thetitle compound, melting point 195-196° C.

Anal. Calc'd. for C₁₆ H₁₀ N₂ O₂ : C, 73.27; H, 3.84; N, 10.68. Found: C,73.43; H, 3.67; N, 10.74.

(b)6,7-dihydro-N,N"-diphenyldibenzo[e,g][1,4]dioxocin-2,11-dicarboximidamide

A slurry of 6,7-dihydrodibenzo[e,g][1,4]dioxocin-2,11-dicarbonitrile(2.62 g), aniline (1.86 g) and sodium hydride (50% in oil, 960 mg) inanhydrous dimethylsulfoxide (30 ml) is stirred at room temperature undernitrogen for 24 hours. The reaction mixture is poured into water and theresultant precipitate collected by filtration. The crude product (4 g)is washed on the filter several times with water. A sample of this crudeproduct (100 mg) is recrystallized from benzene/cyclohexane to yield 75mg of the title compound, melting point 201-205° C, dec.

Anal. Calc'd. for C₂₈ H₂₄ N₄ O₂ : C, 74.98; H, 5.39; N, 12.49. Found: C,74.86; H, 5.55; N, 12.20.

EXAMPLE 7 6,7-Dihydro-N,N"-diphenyldibenzo[e,g][1,4]dioxocin-2,11-dicarboximidamide, hydrochloride (1:2)

A crude sample of6,7-dihydrodibenzo[e,g][1,4]-dioxocin-2,11-dicarbonitrile (2.5 g, seeExample 6A) is recrystallized 3 times from 10% hydrochloric acid toyield 1.5 g of the title compound, melting point 237°-242° C, dec.

Anal. Calc'd. for C₂₈ H₂₄ N₄ O₂ . 2 HCl . 3/4 H₂ O: C, 62.86; H, 5.18;N, 10.48; Cl, 13.25. Found: C, 62.78; H, 5.23; N, 10.27; Cl, 13.19.

EXAMPLE 86,7-Dihydro-N,N"-bis(4-methoxyphenol)dibenzo[e,g]1,4]-dioxocin-2,11-dicarboximidamide

A mixture of 2.62 g of6,7-dihydrodibenzo[e,g][1,4]-dioxocin-2,11-dicarbonitrile (see Example6A), 0.96 g of sodium hydride (50% mineral oil) and 2.46 g ofp-anisidine is prepared in dimethylsulfoxide (15 ml) and stirred undernitrogen for 24 hours at room temperature. The mixture is then pouredinto water and the precipitate which forms is separated by filtration.This compound is recrystallized from methanol to yield 1.5 g of thetitle compound, melting point 343°-345° C, plus a second crop of 500 mg.

Anal. Calc'd. for C₃₀ H₂₈ N₄ O₄ (first crop): C, 68.44; H, 5.74; N,10.64. Found: C, 68.39; H, 5.95; N, 10.38.

EXAMPLE 96,7-Dihydro-N,N"-bis[3-(trifluoromethyl)phenyl]benzo[e,g][1,4]-dioxocin-2,11-dicarboximidamide,hydrochloride (1:2)

A mixture of 2.5g of6,7-dihydrodibenzo[e,g][1,4]-dioxocin-2,11-dicarbonitrile (see Example6A) and sodium hydride (960 mg) is prepared under nitrogen at roomtemperature in dimethylsulfoxide (10 ml). To this is addedm-amino-benzotrifluoride (3.1 g) in dimethylsulfoxide (4 ml) at such arate as to control the tendency of this reaction to foam. The combinedreaction mixture is stirred for 24 hours at room temperature and thenpoured into water. The precipitate which forms is separated byfiltration and washed with water yielding 4.5 g of solid. This iscrystallized by dissolving first in ether followed by gradual additionof cyclohexane with much scratching with a glass rod. In this way 3.5 gof free base, melting point 206°-212° is obtained. A hydrochloride isprepared from this by dissolving in dilute hydrochloric acid (justenough HCl to reach a pH of 5) followed by addition of concentratedhydrochloric acid. The crystalline hydrochloride so obtained is driedfor 24 hours at room temperature over phosphorous pentoxide, yielding2.4g of the title compound, melting point 236°-240° C.

Anal. Calc'd. for C₃₀ H₂₄ N₄ F₆ Cl₂ O₂ +1.5 mole H₂ O: C, 52.64; H,3.98; N, 8.18; Cl, 10.36. Found: C, 52.80; H, 3.80; N, 8.20; Cl, 10.37.

EXAMPLE 10N,N"-Bis(4-fluorophenyl)-6,7-dihydrobenzo[e,g][1,4]dioxocin-2,11-dicarboximidamide,hydrochloride (1:2)

A mixture of 2,5 g of6,7-dihydrodibenzo[e,g][1,4]-dioxocin-2,11-dicarbonitrile (see Example6A) and sodium hydride (960 mg) is prepared in dimethylsulfoxide (10 ml)under nitrogen. To this is added p-fluoroaniline (2.14 g) dissolved in 4ml of dimethylsulfoxide at a rate slow enough to control the foaming ofthe reaction mixture. After addition is complete the reaction mixture isstirred under nitrogen for 24 hours and then poured into water. Theprecipitate which forms is separated by filtration and washed on thefilter with water yielding, after drying, 4.0 g of free base. This isrecrystallized from acetonitrile to yield 2.5 g of pure material,melting point 259°-262°. A hydrochloride is prepared byrecrystallization of the free base from dilute hydrochloric acid,yielding 2.3 g of the title compound, melting point 273°-725° C.

Anal. Calc'd. for C₂₈ H₂₂ F₂ N₄ O₂ 2 HCl H₂ O: C, 58.44; H, 4.55; N,9.74; F, 6.60; Cl, 12.32. Found: C, 58.72; H, 4.55; N, 9.81; F, 6.61;Cl, 12.58.

EXAMPLE 116,6'-Bis(pentyloxy)-N,N"-bis[3-(trifluoromethyl)phenyl][1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

(A) 6,6'-Dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile

Sodium hydride (50% in oil, 1.92 g) is washed with pentane and slurriedin 50 ml of anhydrous dimethylformamide. The slurry is treated with6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (4.72 g), heated at130° C for 2 hours, and treated with 1-bromopentane (6.04 g). Thereaction mixture is heated at 130° C for 3 days and the mixture ispoured into water and extracted with dichloromethane. After washing withwater and brine, the dichloromethane extract is dried over sodiumsulfate and concentrated. The residue is chromatographed on silica gel(800 ml) eluting with hexane/dichloromethane (1:1) to yield 5.4 g of thetitle compound, melting point 70°-71° C.

(b)6,6'-bis(pentyloxy)-N,N"-bis[3-(trifluoromethyl)phenyl]-[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A slurry of sodium hydride (50% in oil, 1.76 g), m-aminobenzotrifluoride(5.91 g) and 6,6'-dipentyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile (6.9 g;additional material is added to the batch of part A) in 50 ml ofanhydrous dimethylsulfoxide is stirred at room temperature for 3 days.The reaction mixture is poured into water and the resultant precipitatecollected by filtration. The dried material is chromatographed on 1liter of silica gel eluting with (1) dichloromethane and (2) 1%methanol/dichloromethane to yield5'-cyano-2',6-bis(pentyloxy)-N-[3-(trifluoromethyl)-phenyl][1,1'-biphenyl]-3-carboximidamide(melting point 74°-75° C after two recrystallizations from cyclohexane).The column is next eluted with 2% methanol/dichloromethane to yield 1.3g of the desired product. Two recrystallizations of this material from1% hydrochloric acid/methanol yields 900 mg of the title compound,melting point 207°-2l0° C.

Anal. Calc'd. for C₃₈ H₄₀ N₄ O₂ F₆ . 2HCl . H₂ O: C, 57.80; H, 5.62; N,7.09; Cl, 8.98. Found: C, 57.80; H, 5.47; N, 6.87; Cl, 9.05.

EXAMPLE 126,6'-Bis(dodecyloxy)-N,N"-bis[3-(trifluoromethyl)phenyl]-[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

(A) 6,6'-Didodecyloxy[1,1'-biphenyl]-3,3'-dicarbonitrile

Sodium hydride (50% in oil, 1.92 g) is washed with pentane and slurriedin 50 ml of anhydrous dimethylformamide. A solution of6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (4.72 g) in 5 ml ofanhydrous dimethylformamide is added to the slurry and the mixture isheated at 150° C for 2 hours, after which 1-bromododecane (9.96 g) isadded. The reaction is heated at 150° C for 3 days and the reactionmixture is poured into water and extracted with dichloromethane. Afterwashing with water and brine, the dichloromethane extract is dried oversodium sulfate and concentrated in vacuo. The residue is chromatographedon silica gel (800 ml) eluting with hexane/dichloromethane (1:1) toyield 7.4 g of the title compound, melting point 94°-95° C.

(b)6,6'-bis(dodecyloxy)-N,N"-bis[3-(trifluoromethyl)phenyl]-[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2)

A slurry of sodium hydride (50% in oil, 1.42 g), m-aminobenzotrifluoride(4.74 g) and 6,6'-dihydroxy[1,1'-biphenyl]-3,3'-dicarbonitrile (7.6 g)in 50 ml of dimethylsulfoxide is stirred at room temperature for 3 days.The reaction mixture is poured into water and the resultant solidcollected by filtration. The dried solid is chromatographed on 1 literof silica gel eluting with (1) dichloromethane, (2) 0.5%methanol/dichloromethane and (3) 2% methanol/dichloromethane to yield5.9 g of desired product, which is treated with 5 ml of concentratedhydrochloric acid and recrystallized from water/methanol to yield 4 g ofthe title compound, melting point 168°-170° C.

Anal. Calc'd. for C₅₂ H₆₈ F₆ N₄ O₂ . 2HCl . H₂ O: C, 63.34; H, 7.36; N,5.68; Cl, 7.19. Found: C, 63.05; H, 7.11; N, 5.71; Cl, 7.37.

What is claimed is:
 1. A compound having the formula ##STR6## or apharmaceutically acceptable salt thereof, wherein R₁ is phenyl or phenylsubstituted with one or two methoxy, halogen or trifluoromethyl groups;and R₂ is hydrogen or alkyl of 1 to 12 carbon atoms.
 2. A compound inaccordance with claim 1 wherein R₂ is hydrogen.
 3. A compound inaccordance with claim 1 wherein R₂ is alkyl.
 4. The compound inaccordance with claim 1 having the name6,6'-dimethoxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 5. The compound in accordance with claim 1 havingthe name6,6'-dihydroxy-N,N"-diphenyl[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 6. The compound in accordance with claim 1 havingthe name6,6'-dimethoxy-N,N"-[3-(trifluoromethyl)phenyl]-[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 7. The compound in accordance with claim 1 havingthe nameN,N"-bis(3,5-dimethoxyphenyl)-6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 8. The compound in accordance with claim 1 havingthe nameN,N"-bis(4-fluorophenyl)-6,6'-dimethoxy[1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 9. The compound in accordance with claim 1 havingthe name6,6'-bis(pentyloxy)-N,N"-bis[3-(trifluoromethyl)-phenyl][1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).
 10. The compound in accordance with claim 1 havingthe name6,6'-bis(dodecyloxy)-N,N"-bis[3-(trifluoromethyl)-phenyl][1,1'-biphenyl]-3,3'-dicarboximidamide,hydrochloride (1:2).